The Zika virus, which is mostly transmitted by Aedes aegypti mosquitoes, emerged around 2007 to cause infections around the world, primarily in Asia, the Americas, and Pacific nations. There was a massive outbreak of Zika in Brazil in 2015, but the infection has largely declined since 2017. There are still outbreaks and infections in endemic regions, however. The 2017 Brazilian epidemic revealed that Zika was particularly dangerous for pregnant women; children born to infected mothers were at risk for microcephaly, or unusually small head size.
Most of the time, Zika infections cause only mild illnesses in adults and older kids. But there is a link to complications like Guillain-Barré syndrome, nerve pain, and inflammation in the spinal cord, or myelitis.
Scientists have now revealed more about how this infection affects human cells. Reporting in the Proceedings of the National Academy of Sciences (PNAS), scientists have shown how the virus hijacks a natural process in cells that clears waste materials away, known as autophagy.
Viruses take advantage of proteins or receptors on the surfaces of human cells to gain entry into those cells, and start an infection. Human cells have receptors that can interact with viral proteins, and once that interaction starts, the viruses can then get into the cells. Sometimes those human cell surface proteins have protective effects too. They can alert the body that the cell is infected, and that the immune system should get to work.
But it seems that once inside a cell, the Zika virus can also manipulate those proteins, so they are no longer expressed on the cell surface - they are downregulated by the virus.
“That’s the most interesting part: It’s amazing that not only one, but several Zika proteins can do this,” said senior study author Shan-Lu Liu, a Professor at The Ohio State University, among other appointments. “We looked at two Zika virus strains and examined three physiologically relevant cell types. With both strains, we could see the downregulation in all three cell types. It looks like this is an important mechanism.”
Previous work has shown that TIM proteins are often critical to viral infection. Some of the TIM proteins, like AXL and TIM-1, can interact with phosphatidylserine (PS) on viruses to facilitate infection. But once infected, AXL and TIM-1 are expressed at lower levels. This is because normally, AXL and TIM-1 would generate inflammatory molecules because of the infection. It would also enable more viral particles to infect the same cell.
Instead, the downregulation of the receptors stops that competition, since Zika has already taken over the cell.
This study also revealed that the virus uses a natural process in cells known as autophagy to downregulate the receptors. There are three Zika virus proteins that can boost autophagy.
Autophagy is a crucial and fundamental process that helps cells break down damaged organelles or problematic proteins. This work has shown how it can be hijacked by a virus.
“The bottom line is this speaks to the co-evolution of viral-host interactions. The more important a host factor is to a virus, the more a virus is going to do to take control of it,” Liu said. “Understanding these mechanisms is an important part of being prepared for emerging or reemerging viruses that cause infectious diseases.”
Recent, unrelated work has also shown that Zika can harness a human brain protein to promote its own growth. This protein, called ANKLE2, is also vital for the development of the human brain. Zika also has a unique ability among viruses: it can cross the placental barrier, and impact the fetal brain and this protein. Those findings were reported in mBio.
Sources: Ohio State University, mBio, Proceedings of the National Academy of Sciences (PNAS)